Synthetic Modification of Carboxymethylcellulose and Use Thereof to Prepare a Nanoparticle Forming Conjugate of Docetaxel for Enhanced Cytotoxicity against Cancer Cells

Abstract

A nanoparticle formulation of docetaxel (DTX) was designed to address the strengths and limitations of current taxane delivery systems: PEGylation, high drug conjugation efficiency (>30 wt %), a slow-release mechanism, and a well-defined and stable nanoparticle identity were identified as critical design parameters. The polymer conjugate was synthesized with carboxymethylcellulose (CMC), an established pharmaceutical excipient characterized by a high density of carboxylate groups permitting increased conjugation of a drug. CMC was chemically modified through acetylation to eliminate its gelling properties and to improve solvent solubility, enabling high yield and reproducible conjugation of DTX and poly(ethylene glycol) (PEG). The optimal conjugate formulation (Cellax) contained 37.1 ± 1.5 wt % DTX and 4.7 ± 0.8 wt % PEG, exhibited a low critical aggregation concentration of 0.6 μg/mL, and formed 118-134 nm spherical nanoparticles stable against dilution. Conjugate compositions with a DTX degree of substitution (DS) outside the 12.3-20.8 mol % range failed to form discrete nanoparticles, emphasizing the importance of hydrophobic and hydrophilic balance in molecular design. Cellax nanoparticles released DTX in serum with near zero order kinetics (100% in 3 weeks), was internalized in murine and human cancer cells, and induced significantly higher toxic effects against a panel of tumor cell lines (2- to 40-fold lower IC50 values) compared to free DTX.

Docetaxel Conjugate Nanoparticles That Target α-Smooth Muscle Actin–Expressing Stromal Cells Suppress Breast Cancer Metastasis

“…We have developed an enhanced drug delivery approach for docetaxel, and have previously shown that Cellax nanoparticles were effective in enhancing the pharmacokinetics, safety, and efficacy of docetaxel in subcutaneous and orthotopic mouse models of cancer (14)(15)(16)(17). In this study, our analysis of Cellax efficacy in orthotopic breast models led to the discovery that Cellax interacts with a-SMAþ stromal cells, leading to increased tumor permeability and perfusion, reduced IFP, and inhibition of metastases.…”

“…Cellax polymer and particles (including DiI-containing particles) were prepared as described previously (14)(15)(16)(17). Additional reagents are described in Supplementary Material.…”

“…Additional reagents are described in Supplementary Material. Cellax particle size and zeta potential were measured on a Malvern NanoZS instrument, and docetaxel content was measured by a UV method (14,15). The Cellax particles were sterile filtered through a 0.22 mm filter and tested for endotoxin using the Limulus amebocyte lysate (LAL) turbidity assay and sterility was determined using the agar plate assay (Nanotechnology Characterization Lab).…”

Nanomedicine: The Promise and Challenges in Cancer Chemotherapy

“…This formulation (Cellax) was shown to be more effi cacious than commercial solvent-based docetaxel and nab-paclitaxel in both in vitro and in vivo studies [ 194 -197 ]. Docetaxel conjugation percentage was high (>30 wt %), and it was completely and slowly released following a near zero-order pattern within 3 weeks [ 197 ]. In a recent study that thoroughly investigates the tumor stroma involvement in the anticancer activity of Cellax, the authors reported that Cellax signifi cantly depleted the stroma of orthotopically implanted mammary tumors (4T1 and MDA-MB-231), with an about 70-fold increase in tumor perfusion and about 3-fold suppression of IFP, while minimum or no effect was noticed following either solvent-based docetaxel or nab-paclitaxel, in the same tumor models [ 169 ].…”

Syntheses of new antimicrobial cellulose materials based 2-((2-aminoethyl)amino)-4-aryl-6-indolylnicotinonitriles

“…It widely used in many industrial pharmaceutics, cosmetics, drug delivery, and wound dressing because of their high water absorption property, gelation behavior, bio-degradability, and biocompatibility [20][21][22]. Additionally, Schiff bases has received great attention due to their reported biological activities [23,24].…”